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Ball mass is an important parameter that is known to have an influence on the outcome of a mechanochemical reaction induced by ball-milling. A standard way of modifying the ball mass is to change the size of the ball made of the same material. In this case, however, a change in mass is accompanied by a simulatneous change in the ball size. It is therefore not possible to disentangle the effects of mass and Surface area in these cases. In the present work we report the results of experiments with specially designed and manufactured balls in which (1) milling ball mass is held constant, but their size differs, and (2) the ball mass is altered, with the diameter of the milling ball being held constant. Using the cocrystallisation of theophylline + nicotinamide as a case study it was found that both diameter and ball mass play crucial roles in determining the rate of a mechanochemical reaction. For comparison, we have also used milling balls with the same size (different mass), and others with the same mass (different size) made of different materials, as would be “traditional”. It was found that, despite having the same size, the lightest milling ball (nylon) was the most efficient in initiating the co-crystallisation, presumably due to the sorption of EtOH. Hence, the results of this manuscript also demonstrate how milling ball material can in fact be the most influential parameter, and potentially counterintuitive to classical mechanics.
Mechanochemistry offers a unique opportunity to modify and manipulate crystal forms, often providing new products as compared with conventional solution methods. While promising, there is little known about how to control the solid form through mechanochemical means, demanding dedicated investigations. Using a model organic cocrystal system (isonicotinamide:glutaric acid), we here demonstrate that with mechanochemistry, polymorphism can be induced in molecular solids under conditions seemingly different to their conventional thermodynamic (thermal) transition point. Whereas Form II converts to Form I upon heating to 363 K, the same transition can be initiated under ball milling conditions at markedly lower temperatures (348 K). Our results indicate that mechanochemical techniques can help to reduce the energy barriers to solid form transitions, offering new insights into controlling polymorphic forms. Moreover, our results suggest that the nature of mechanochemical transformations could make it difficult to interpret mechanochemical solid form landscapes using conventional equilibrium-based tools.
Unintended Rate Enhancement in Mechanochemical Kinetics by Using Poly(methyl methacrylate) Jars
(2022)
Time-resolved in situ (TRIS) X-ray diffraction has changed how mechanochemical transformations are studied but requires the use of X-ray transparent jars often made from poly(methyl methacrylate) (PMMA). However, using PMMA jars can alter the apparent kinetics of mechanochemical polymorphism by an order of magnitude, questioning the interpretability of established TRIS methods. Our results suggest that rate enhancement in PMMA jars may not be dominated by chemical effects of the polymer, but rather a result of different equilibrium temperatures within the jar. These features must be better understood before control over mechanochemical reactions can be achieved.
The mechanochemical formation of the ionic cocrystals of glucose (Glc) and sodium salts Glc2NaCl·H2O (1) and Glc2NaX (X = Br (2), I (3)) is presented. Products are formed by co-milling Glc with three sodium salts (NaCl, NaBr, NaI). The ionic cocrystals were obtained under both neat grinding and liquid-assisted grinding conditions, the later found to accelerate the reaction kinetics. The crystal structures of the ionic cocrystals (2) and (3) were solved from powder X-ray diffraction data. The structure solution contrasts with the structure of Glc2NaCl·H2O (1) where the electron density at three halide crystallographic sites is modeled as of being the intermediate between water molecule and a chloride ion. The reaction pathways of the three ionic cocrystals were investigated in real time using our tandem approach comprising a combination of in situ synchrotron powder X-ray diffraction and Raman spectroscopy. The results indicate the rapid formation of each cocrystal directly from their respective starting materials without any intermediate moiety formation. The products were further characterized by DTA-TG and elemental analysis.
Pirfenidone is an important drug molecule used in the treatment of idiopathic lung fibrosis. Although approved by the USFDA in 2014, pirfenidone’s aqueous solubility is too high and must be mitigated by additives. In this work, the cocrystallization of pirfenidone is explored as an alternative approach to reducing its solubility. Herein, an anhydrous form of pirfenidone is reported, alongside its first two reported cocrystals. The new crystalline solids are thoroughly characterized by single crystal X-ray diffraction (SCXRD), powder X-ray diffraction analysis (PXRD), Fourier transform infrared (FTIR) spectroscopy, differential scanning calorimetry (DSC), and thermogravimetric analysis (TGA).
Equilibrium solubility and intrinsic dissolution rates (IDR) are studied for the cocrystals and compared to that of the parent drug. Both cocrystal forms exhibit drastically lower aqueous solubility (by up to 90%) and dissolution rates, rationalized based on both lattice energy calculations and consideration of intermolecular interactions in the solid state. Furthermore, we compare the physicochemical properties of solution-based material with that of material produced mechanochemically. Importantly, no differences are observed between the two production methods. This work demonstrates the strength of crystal Engineering strategies to beneficially modify important pharmaceutical properties and highlights the potential of mechanochemistry to facilitate this in an environmentally benign way.
The mechanism of ternary cocrystal formation, and the potential role of intermediate binary phases, has been debated for some time. We report here the first in situ real-time monitoring of two prototypic ternary cocrystals. Our results suggest that the question is more complicated than previously considered. The mechanism of mechanochemical ternary cocrystal formation depends on the milling conditions, here the milling frequency and addition of liquid. Binary phases can form under certain conditions, but do not act as intermediates in the formation of the ternary cocrystals. Rather, binary phases are competitive with the ternary phase, and their formation appears to compete with that of the ternary components. The presence of binary phases leads to an increase in the overall reaction time. The results reported here offer the first insights into the true complexities of mechanochemical multi-component synthesis of higher order multi-component crystals and demonstrate a new understanding of the influence of milling condition for the study of mechanisms and kinetics.
Mechanochemistry has become a valuable method for the synthesis of new materials and molecules, with a particular strength for screening and preparing multicomponent crystals. In this work, two novel cocrystals of pyrazinamide (PZA) with pimelic acid (PA) were prepared mechanochemically. Their formation was monitored in real time by in situ synchrotron powder X-ray diffraction. Control over the polymorphic form was obtained through the selective choice of liquid additive via liquid assisted grinding. Slurry experiments and dispersion-corrected density functional theory calculations suggest that Form I is the thermodynamically stable form under ambient conditions. Upon aging, Form II converts to Form I. The stability of Form II upon aging was found to depend strongly on the milling duration, intensity, and material of the milling vessels. Longer or higher energy milling drastically increased the lifetime of the Form II product. For the first time, this work also demonstrates that the choice of milling jar can have a decisive effect on the aging stability of a bulk polymorphic powder. In contrast to material prepared in steel milling vessels, the preparation of Form II in Perspex (PMMA) vessels increased its lifetime 3-fold. These findings offer a new dimension to garnering control over mechanochemical cocrystallization and demonstrate the critical importance of the careful and timely ex situ screening of ball mill grinding reactions. This will be of importance for potential industrial applications of mechanochemical cocrystallization where understanding polymorph longevity is crucial for the development of a robust preparative protocol.
The very strong Lewis acid aluminium chlorofluo-ride (ACF) was loaded with anhydrous HF. The interactionbetween the surface of the catalyst and HF was investigatedusing a variety of characterization methods, which revealed he formation of polyfluorides. Moreover, the reactivity ofthe HF-loaded ACF towards the hydrofluorination of alkyneswas studied.
The transformation of a base-catalyzed, mechano-assisted Knoevenagel condensation of mono-fluorinated benzaldehyde derivatives (p-, m-, o-benzaldehyde) with malonodinitrile was investigated in situ and in real time. Upon milling, the para-substituted product was found to crystallize initially into two different polymorphic forms, depending on the quantity of catalyst used. For low catalyst concentrations, a mechanically metastable phase (monoclinic) was initially formed, converting to the mechanically stable phase (triclinic) upon further grinding. Instead, higher catalyst concentrations crystallize directly as the triclinic product. Inclusion of catalyst in the final product, as evidenced by mass spectrometric analysis, suggests this complex polymorphic pathway may be due to seeding effects. Multivariate analysis for the in situ Raman spectra supports this complex formation pathway, and offers a new approach to monitoring multi-phase reactions during ball milling.
Tuning and controlling the solid-state photophysical properties of organic luminophore are very important to develop next-generation organic luminescent materials. With the aim of discovering new functional luminescent materials, new cocrystals of 9-anthracene carboxylic acid (ACA) were prepared with two different dipyridine coformers: 1,2-bis(4-pyridyl)ethylene and 1,2-bis(4-pyridyl)ethane. The cocrystals were successfully obtained by both mechanochemical approaches and conventional solvent crystallization. The newly obtained crystalline solids were characterized thoroughly using a combination of single crystal X-ray diffraction, powder X-ray diffraction, Fourier-transform infrared spectroscopy, differential thermal analysis, and thermogravimetric analysis. Structural analysis revealed that the cocrystals are isostructural, exhibiting two-fold interpenetrated hydrogen bonded networks. While the O–H···N hydrogen bonds adopts a primary role in the stabilization of the cocrystal phases, the C–H···O hydrogen bonding interactions appear to play a significant role in guiding the three-dimensional assembly. Both π···π and C–H···π interactions assist in stabilizing the interpenetrated structure. The photoluminescence properties of both the starting materials and cocrystals were examined in their solid states. All the cocrystals display tunable photophysical properties as compared to pure ACA. Density functional theory simulations suggest that the modified optical properties result from charge transfers between the ACA and coformer molecules in each case. This study demonstrates the potential of crystal engineering to design solid-state luminescence switching materials through cocrystallization.